3.2　Target Microenvironment in Tumor

Tumorigenesis is a complex and dynamic process consisting of distinct characteristics responsible for tumor growth and dissemination.These distinguishing features account for tumor complexity and consist of: increased proliferative signals, evasion from growth suppressor, resisting apoptosis,unlimited multiplication, stimulating angiogenesis, promoting invasion and metastasis, modulating cells metabolism and evading immune destruction.These features are acquired through cooperation among different cellular and non-cellular elements of tumors defining the tumor microenvironment(TME).TME consists of non malignant cells of the tumor such as cancer-associated fibroblasts(CAFs), endothelial cells and pericytes composing tumor vasculature, immune and inflammatory cells, bone marrow derived cells, and the extracellular matrix (ECM) establishing a complex cross-talk with tumor (Figure 3.4).Incipient neoplastic cells, in fact, recruit and activate some stromal cells, which in turn activate biological signals that permit cancer cells to invade surrounding normal tissue and to metastasize in distant organ.Tumor cells metastasizing in a tissue different from original can survive and expand in normal microenvironment or meet a favorable microenvironment (pre-metastatic niches), positively pre-conditioned before the arrival of tumoral cells from several conditions such as circulating factors released by primary tumors [28].

(https://www.daowen.com)

Figure 3.4　Anatomy of th e tumor mi croenvironment (T ME).(A) The TME of a late stage solid tumor is highly heterogeneous and complex.(B) Exosomes play important roles in paracrine and autocrine communication between TME cells, being preponderant in the modulation and development of the tumor.Exosomes are also involved in the transformation of normal cells adjacent to the TME into tumor cells.The extracellular matrix (ECM) in the TME is frequently dense and stiff, resulting in desmoplasia.(C) The rapid growth of tumor cells results in hypoxic regions and lack of nutrients within the tumor, causing the Warburg effect.This metabolic shift into anaerobic glycolytic pathway results in acidification of the TME.(D) The rapid growth of tumor cells induces angiogenesis and consequent formation of chaotic branching structures.Stromal cells (including Cancer-associated fibroblasts and mesenchymal stromal cells) and cells from the immune system (both lymphoid and myeloid lineage cells) are important players in tumor development and prognosis.(Please scan the QR code on the Preface to get original color figures.)
Source: Roma-Rodrigues C, Mendes R, Baptista P V, Fernandes A R.“Targeting tumor microenvironment for cancer therapy”.InternationalJournalofMolecularSciences, 2019, 20:840.